COMPOSE

COMPOSE – DP-1111-02

ITM Solucin GmbH, Germany

Well-differentiated aggressive G2 and G3 GEP-NETs

Prospective, randomised (1:1), controlled, open-label, multi-centre, international, Phase III study.

Phase III study

A total of 220 patients will be randomised into the study (see Rationale for Number of Patients below).

Investigateur principal pour la France : Thomas Walter (Lyon)

Mail Walter

Centres français:  Lyon, Nantes, Toulouse, Bordeaux …

Primary Objective

To demonstrate the efficacy of PRRT with 177Lu-Edotreotide in the treatment of aggressive G2 (15 < Ki‑67 ≤ 20) and Grade 3 (20 < Ki-67 ≤ 55) SSTR+ GEP-NETs compared to best standard of care (investigator’s choice [among the protocol comparator list]).

Secondary Objectives

1. To assess the impact of PRRT with 177Lu-Edotreotide on study patient’s health-related quality of life (HRQL) and neuroendocrine carcinoid tumour symptoms during and after therapy (European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaire [QLQ]-C30 and GI.NET21) in comparison to best standard of care.
2. To assess the safety and tolerability of PRRT with 177Lu-Edotreotide in study patients compared to control treatment options.

• Provided written informed consent.
• Patients aged ≥ 18 years.
• Histologically confirmed diagnosis of unresectable (with curative intent), well-differentiated neuroendocrine tumour of gastroenteric or pancreatic origin (GEP-NET), with a Ki-67 index 15 or above and below or equal to 55.
• In the investigator’s opinion, eligible to receive at least one of the following: CAPTEM, Everolimus or FOLFOX as per the Prescribing Information/Summary of Product Characteristics and local protocols in the respective study regions.
• Availability of existing biopsy specimen from primary tumour or metastasis or, if unavailable, willingness to undergo current biopsy for analysis.
• At least 1 measurable site of disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 using contrast computed tomography (CT)/magnetic resonance imaging (MRI). Patients who are allergic to intravenous (IV) contrast may be imaged without. • SSTR+ disease, as evidenced by 68Ga-based or 64Cu-based (if approved according to local regulations) SSTR positron emission tomography (PET) imaging (68Ga‑edotreotide, 68Ga-DOTATATE or 64Cu-DOTATATE) imaging within 4 months prior to randomisation.
  – The majority of the CT/MRI lesions have to be SSTR+.
  – The majority of fluorodeoxyglucose (FDG) PET-positive lesions have to be SSTR-positive.
  – Time between the SSTR PET and FDG PET should be ≤ 14 days.
• Maximum of one prior line of therapy (including somatostatin analogues [SSAs]). Patients who progress on treatment with SSAs, may remain on treatment if in the investigator’s opinion this is required to control symptoms of carcinoid syndrome.
• Second-line patients must have disease progression (radiological [according to RECIST v1.1] and/or biochemical [defined as two consecutive measurements in NET hormone levels both of which are increased by ≥30%]) on first-line therapy within the 6 months prior to study entry (i.e. randomisation).
• Karnofsky performance status (KPS) scale ≥ 60.

• Known hypersensitivity to lutetium-177, Edotreotide, the comparator or any other component of the comparator.
• Known hypersensitivity to lysine, arginine, or any excipient of the nephroprotective amino acid solution given concurrently with the 177Lu-Edotreotide infusion.
• Prior external beam radiation therapy (EBRT) to more than 25% of the bone marrow.
• Prior selective internal radiation therapy (SIRT).
• Prior peptide receptor radionuclide therapy (PRRT).
• Prior therapy with chemotherapy, mammalian target of rapamycin (mTOR) inhibitors, vascular endothelial growth factor (VEGF) pathway inhibitors, immunotherapy, interferon, chemo-embolisation, bland embolisation, cyclosporine A, locoregional treatment (e.g. cytoreduction surgery, radiofrequency ablation [RFA], liver directed intra-arterial intervention), or any change in the SSA posology (only patients who are continuing with SSAs for the control of carcinoid symptoms), within 4 weeks prior to randomisation into the study.
• Any other surgery within 4 weeks prior to randomisation in the study.
• Therapy with an investigational compound and/or medical device within 30 days or 7 half-life periods (whichever is longer) prior to randomisation.
• Patients who have received a live vaccine up to 4 weeks prior to first dose.
• Received any prohibited medication (as defined in the study protocol).
• Ongoing haematological or renal Grade 2 toxicity or other Grade 3 toxicity from previous standard or investigational therapies (National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version 4.03).
• Patients with brain metastases.
• Other known co-existing malignancies, except non-invasive skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
• Serious non-malignant disease (e.g. psychiatric, infectious, autoimmune or metabolic), that may interfere with the objectives of the study or with the safety or compliance of the patient, as judged by the investigator.
• Renal, hepatic, cardiovascular, or haematological organ dysfunction, potentially interfering with the safety of the study treatments, as follows:
• Renal
  – Creatinine clearance < 40 mL/min calculated by the Cockcroft Gault method
  – Glomerular filtration rate (GFR, CKD-EPI) < 40 mL/min/1.73 m2 (local laboratory)
  – Renal tract obstruction
• Hepatic
  – Total bilirubin > 3 × upper limit of normal (ULN)
  – Albumin < 3 g/dL
  – Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 5 × ULN
  – Known ascites
• Cardiovascular
  – New York Heart Association classification III and IV
  – Uncontrolled hypertension
• Haematopoietic
  – Platelets ≤ 75 × 109/L
  – Absolute neutrophil count (ANC) < 1.5 × 109 cells/L
  – Haemoglobin (Hb) concentration < 5.0 mmol/L (< 8.0 g/dL)
• Current spontaneous urinary incontinence.
• Pregnancy or lactation.
• Pregnant or breast-feeding women. Female patients of childbearing potential or male patients with female partners of childbearing potential, unless willing to practice full and true sexual abstinence or who are surgically/permanently sterile (bilateral tubal occlusion, hysterectomy, or vasectomy), or female patients whose male partners have medically successful vasectomy (provided the partner is the sole sexual partner of the female patient of childbearing potential), or who are not willing to practice highly effective contraception in combination with a barrier method of contraception (e.g. condom). Contraception methods that are considered highly effective are: oral or non-oral (injected or implanted) non-oestrogen progesterone-based hormonal method; oral, intravaginal, or transdermal combined oestrogen and progesterone-based hormonal methods; and/or intrauterine device (IUD), and/or intrauterine hormone-releasing system (IUS). Sexual abstinence or the contraception methods described above must be followed throughout the entire study period and for the following durations after the last treatment cycle: 6 months for CAPTEM; 8 weeks for Everolimus; 6 months for FOLFOX; 66 days for PRRT (10 half-lives of 177Lu).
• Patients not able to declare meaningful informed consent on their own (e.g. with legal guardian for mental disorders) or any other vulnerable population to that sense (e.g. persons institutionalised, incarcerated etc.).